Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface.

Many secretory enzymes acquire essential zinc ions (Zn) in the Golgi complex. ERp44, a chaperone operating in the early secretory pathway, also binds Zn to regulate its client binding and release for the control of protein traffic and homeostasis. Notably, three membrane transporter complexes, ZnT4, ZnT5/ZnT6 and ZnT7, import Zn into the Golgi lumen in exchange with protons.

Endoplasmic reticulum oxidoreductase 1 alpha modulates prostate cancer hallmarks.

Background: Therapies available for late stage prostate cancer (PCa) patients are limited and mostly palliative. The necessary development of unexplored therapeutic options relies on a deeper knowledge of molecular mechanisms leading to cancer progression. Redox signals are known to modulate the intensity and duration of oncogenic circuits; cues originating from the endoplasmic reticulum (ER) and downstream exocytic organelles are relevant in secretory tumors, including PCa.

A virtuous cycle operated by ERp44 and ERGIC-53 guarantees proteostasis in the early secretory compartment.

The composition of the secretome depends on the combined action of cargo receptors that facilitate protein transport and sequential checkpoints that restrict it to native conformers. Acting after endoplasmic reticulum (ER)-resident chaperones, ERp44 retrieves its clients from downstream compartments. To guarantee efficient quality control, ERp44 should exit the ER as rapidly as its clients, or more.

The pivotal role of ERp44 in patrolling protein secretion.

Interactions between protein ligands and receptors are the main language of intercellular communication; hence, how cells select proteins to be secreted or presented on the plasma membrane is a central concern in cell biology. A series of checkpoints are located along the secretory pathway, which ensure the fidelity of such protein signals (quality control). Proteins that pass the checkpoints operated in the endoplasmic reticulum (ER) by the binding immunoglobulin protein (BiP; also known as HSPA5 and GRP78) and the calnexin-calreticulin systems, must still overcome additional scrutiny in the ER-Golgi intermediate compartment (ERGIC) and the Golgi.

Zinc regulates ERp44-dependent protein quality control in the early secretory pathway.

Zinc ions (Zn) are imported into the early secretory pathway by Golgi-resident transporters, but their handling and functions are not fully understood. Here, we show that Zn binds with high affinity to the pH-sensitive chaperone ERp44, modulating its localization and ability to retrieve clients like Ero1α and ERAP1 to the endoplasmic reticulum (ER). Silencing the Zn transporters that uptake Zn into the Golgi led to ERp44 dysfunction and increased secretion of Ero1α and ERAP1.